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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age
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Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age

机译：STAT3限制心肌细胞的敲除导致高龄者对炎症，心脏纤维化和心力衰竭的敏感性更高

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摘要

Cytokines and inflammation have been implicated in the patho-genesis of heart failure. For example, IL-6 family cytokines and the gp130 receptor play important roles in cardiac myocyte survival and hypertrophy. Signal transducer and activator of transcription 3 (STAT3) is a major signaling protein that is activated through gp130. We have created mice with a cardiomyocyte-restricted deletion of STAT3. As measured by serial echocardiograms, mice with cardiac specific deletion of STAT3 are significantly more susceptible to cardiac injury after doxorubicin treatment than age-matched controls. Intriguingly, STAT3 appears to have a critical role in protection of inflammation-induced heart damage. STAT3-deficient mice treated with lipopolysaccharide demonstrated significantly more apoptosis than their WT counterparts. At the cellular level, cardiomyocytes with STAT3 deleted secrete significantly more tumor necrosis factor α in response to lipopolysaccharide than those with WT STAT3. Furthermore, histologic examination of the cardiomyocyte-restricted STAT3-deficient mice reveals a dramatic increase in cardiac fibrosis in aged mice. Although no overt signs of heart failure are present in young STAT3-deficient mice, they spontaneously develop heart dysfunction with advancing age. These results indicate the crucial functions of STAT3 in cardiomyocyte resistance to inflammation and other acute injury and in pathogenesis of age-related heart failure.
机译：细胞因子和炎症与心力衰竭的发病机理有关。例如，IL-6家族细胞因子和gp130受体在心肌细胞存活和肥大中起重要作用。信号转导和转录激活因子3（STAT3）是一种主要的信号蛋白，可通过gp130激活。我们创建了具有心肌细胞限制的STAT3缺失的小鼠。通过连续超声心动图测量，与年龄匹配的对照组相比，阿霉素治疗后具有心脏特异性STAT3缺失的小鼠对心脏损伤的敏感性更高。有趣的是，STAT3在保护炎症引起的心脏损害中起着至关重要的作用。用脂多糖治疗的STAT3缺陷小鼠比野生型WT小鼠显示出明显更多的凋亡。在细胞水平上，缺失STAT3的心肌细胞对脂多糖的反应分泌的肿瘤坏死因子α明显高于WT STAT3。此外，心肌细胞受限的STAT3缺陷小鼠的组织学检查显示，老年小鼠心脏纤维化显着增加。尽管在年轻的STAT3缺陷型小鼠中没有明显的心力衰竭迹象，但随着年龄的增长，它们会自发发展为心脏功能障碍。这些结果表明STAT3在心肌细胞对炎症和其他急性损伤的抗性以及与年龄有关的心力衰竭的发病机理中的关键功能。

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